Hepsin is a type II transmembrane serine protease (TTSP) expressed on the surface of epithelial cells. The 417-amino acid protein is composed of a short N-terminal cytoplasmic domain, a transmembrane domain and a single scavenger receptor cysteine-rich domain that packs tightly against the C-terminal protease domain (1). The physiologic function of HEPSIN is unclear. Despite its expression in the very early stages of embryogenesis (2), HEPSIN-deficient mice were viable and developed normally (3,4). HEPSIN was found not to be essential for liver regeneration and for coagulation-related physiological functions (3,4). However, HEPSIN has been implicated in ovarian [(5); WO2001/62271] and prostate cancer. Several gene expression studies identified HEPSIN as one of the most highly induced genes in prostate cancer (6-11). Hepsin RNA levels were found to be low in normal prostate and benign hyperplasia, but strongly increased in prostate carcinoma, particularly in advanced stages (8-10). Hepsin protein staining with a monoclonal anti-HEPSIN antibody showed that HEPSIN expression was highest at sites of bone metastasis and in late stage primary tumors (12), which is consistent with the finding that increased HEPSIN RNA levels correlated with higher Gleason grades and tumor progression (7-10,13).
Experimental evidence for a role of HEPSIN in prostate cancer came from a recent study by Klezovitch et al. (14) demonstrating that in a mouse model of non-metastasizing prostate cancer, overexpression of HEPSIN led to primary tumor progression and metastasis. Intriguingly, HEPSIN overexpression was associated with basement membrane disruption (14) pointing towards the possibility that HEPSIN activity is somehow linked to the degradation of basement membrane components. In-vitro, HEPSIN is able to convert the latent growth factor pro-hepatocyte growth factor (pro-HGF) into its active two-chain form (HGF), which induced Met receptor signaling [(15); (16); WO2006/014928]. Because the HGF/Met pathway has been implicated in invasive tumor growth and metastasis, it is possible that overexpression of HEPSIN activates the HGF/Met axis in prostate cancer (15,16). Hepsin was also shown to cleave other substrates in-vitro, mainly coagulation-related proteins (15,17). However, their role in tumorigenesis is not known.
The strong expression of HEPSIN in prostate and other cancers makes it an attractive diagnostic marker for a variety of diseases, in particular cancers. Furthermore, other members of the TTSP family, such as matriptase and TMPRSS2 are shed from cell surfaces and shed matriptase has been detected in human breast milk (18). Based on the structural similarity with these TTSPs, it is possible that tumor-derived HEPSIN could be detected in human body fluids using appropriate detection systems.
It is evident that HEPSIN expression is associated with, and likely plays a role in the etiology of, various diseases. HEPSIN expression is associated with various characteristics of diseases, such as particular stages and extent of malignancy of cancers. One of the most difficult challenges in clinical management of complex diseases such as cancer is the accurate and early identification of the diseases in a patient. Thus, although some antibodies have been generated that apparently bind HEPSIN (e.g., Tsuji et al., J. Biol. Chem. (1991), 266(25):16948-16953; Torres-Rosado et al., Proc. Natl. Acad. Sci. USA (1993), 90:7181-7185; WO2004/035733; WO2002/064839; WO2004/033630), it is clear that it would be beneficial to have compositions and methods that are effective and flexible in detecting and/or targeting HEPSIN in vitro and in vivo. The invention provided herein relate to such compositions and methods.
All references cited herein, including patent applications and publications, are incorporated by reference in their entirety.